Vancomycin is an antibiotic which was initially discovered in the 1950's, see U.S. Pat. No. 3,067,099. It is usually reserved for use in the treatment of severe gram positive infections such as those caused by Staphylococcus aureus and when traditional antibiotics have failed. Over the years, there have been several proposals for improving one or more attributes of vancomycin, usually by continuous infusion. In another example, prodrugs of vancomycin have been proposed as a way of increasing the solubility and circulating life of the drug.
Prodrugs include chemical derivatives of a biologically-active parent compound which, upon administration, will eventually liberate the active parent compound in vivo. The use of prodrugs allows the artisan to modify one or more properties such as the onset and/or duration of action of a biologically-active compound in vivo. Prodrugs are often biologically inert or substantially inactive forms of the active compound. The rate of release of the active drug is influenced by several factors including the rate of hydrolysis of the linker which joins the parent biologically active compound to the prodrug carrier.
Polymer conjugates of vancomycin have also been proposed as potential prodrugs. For example, commonly-assigned U.S. Pat. No. 6,180,095 discloses benzyl elimination (BE) systems as part of a tripartite polymer-based prodrug platform. These BE prodrug systems are designed inter alia to releasably attach polymers such as polyethylene glycol (hereinafter PEG) to hydroxyl or amine residues on small molecules. After administration to a patient, the prodrugs break down in a predictable fashion. First, the polymer portion hydrolyzes at a predictable, predetermined rate due to the presence of selected bifunctional linkers which contain the desired “trigger”. Once the polymer portion has been hydrolyzed, the BE system is initiated or triggered and rapidly releases the parent compound. Commonly assigned U.S. Pat. Nos. 5,965,119 and 6,303,569 disclose related tripartate prodrug systems containing trimethyl lock triggers. Commonly assigned U.S. Patent application 60/425,892 discloses mono and di-substituted polymeric prodrugs employing releasably linked platforms. Commonly assigned U.S. Pat. No. 6,395,266 discloses a branched polymeric platform system useful for multiple loading of biologically active moieties. Commonly assigned U.S. Pat. Nos. 6,127,355 and 5,965,566 disclose high molecular weight polymer conjugates as drug delivery systems. Commonly assigned U.S. Patent Applications 60/425,890 and 60/425,892 disclose methods of making releasable polymeric vancomycin derivatives. In the aforementioned applications, the polymer platform is attached at either one or both of the sugar amine group and the N-methyl amine group of the vancomycin or vancomycin derivative. The disclosure of each of the above-mentioned commonly-assigned patents and applications is incorporated herein by reference.
In spite of the fact that vancomycin is listed among the various biologically active compounds having an available amino group for attachment of the prodrug platform in each of the foregoing commonly-assigned patents, further advances have been sought to refine and improve vancomycin therapies. In the past, it was thought that using permanent bonds, i.e. those substantially resistant to hydrolysis, to attach the vancomycin to a polymer such as PEG would not provide sufficiently active compounds. It has now been discovered that attachment of polymeric platforms through amide, urea, carbamate or other similar hydrolysis-resistant bonds is advantageous and can provide additional prodrugs. The vancomycin prodrugs of the present invention, have been shown to hydrolyze and liberate vancomycin in vivo over an extended period of time. Advantages of these types of prodrugs include, extended circulating life due to very slow hydrolysis of the polymer portion to release native drug and a more efficient cost effective manufacturing process. New versions of prodrugs capable of maintaining efficacy and reducing negative side effects while maintaining cost effectiveness is an ongoing need. This invention addresses such needs.